TRP channels of various metazoans mediate nearly every sensory modality, including thermal, mechanical, visual and chemical (i.e., taste and vomeronasal). A gain-of-function mutation in the Trpml3 gene causes deafness and other defects in the Varitint-waddler mouse. We have found that Trpml3 is expressed in hair cells of the inner ear as well as in another type of primary sensory neuron. The long-term goal of this research is to determine what the function of Trpml3 is in two types of sensory receptor cells. I propose to determine the function of Trpml3 in these sensory cells using a Trpml3 conditional knockout mouse I have made. I will generate mice in which Trpml3 is conditionally deleted in hair cells (before and after their development), as well as mice in which Trpml3 is deleted in other sensory neurons. I will then determine the effects of Trpml3 deletion on the anatomy of hair cells and sensory neurons (using light and scanning electron microscopy) and on their sensory function (using behavioral as well as physiological tests such as Auditory Brainstem Responses). Theses studies aim to elucidate Trpml3's function within sensory cells of the inner ear and in other primary sensory neurons. PUBLIC HEALTH RELEVANCE: Currently there is still much to be learned about the auditory process in the ear and in other sensory organs. When the molecular components and their functions in sensory processing is more thoroughly understood it will lead to a better understanding of all how all the mechanisms work together in order to mediate sensory transduction and elicit appropriate responses, which will lead to better prevention, diagnosis and treatment in sensory disorders.